New Therapy for Rare Cancer that Targets the Young

After years of rigorous research, a team of scientists has identified the genetic engine that drives a rare form of liver cancer. The findings offer prime targets for drugs to treat the usually lethal disease, fibrolamellar hepatocellular carcinoma (FL-HCC), which mainly strikes adolescents and young adults.

Sanford Simon, who conducted the research as head of the Rockefeller University’s Laboratory of Cellular Biophysics, describes the culprit as a ‘chimeric gene,’ a mutation created when two genes fuse together. These genes normally sit far apart from each other, separated by some 400,000 base pairs, the building blocks of DNA that combine to form genes.

The chimeric gene, which Simon’s lab first characterised three years ago, has been found in each of the hundreds of FL-HCC patients tested for the mutation.

Having confirmed the chimeric gene as a hallmark of the disease, Simon set out to explore if and how it may cause these malignant tumours. He worked with Scott Lowe, a Cancer Geneticist at the Memorial Sloan Kettering Cancer Centre, to develop a mouse model of FL-HCC.

In work published in the Proceedings of the National Academy of Sciences, the scientists used CRISPR gene editing, a highly precise tool for manipulating DNA, to generate mice that carry the 400,000 base-pair deletion and produce the chimeric gene.

Edward Kastenhuber, a graduate student in Lowe’s lab, found that these mice develop liver tumors that mimic the biology of the tumors found in humans with FL-HCC, suggesting that the deletion is in itself sufficient to cause the cancer – other alterations are not necessary for tumours to grow.

However, this experiment left open the question of precisely how the deletion spurs cancer: by eliminating genes that normally would suppress the growth of tumours, or by introducing the chimeric gene. Another experiment, in which mice with the fused gene but no deletion in the genome developed tumours, proved that it’s the mutation, not the missing DNA as such, that causes the disease.

With the chimeric gene firmly established as the driver of the disease, and its cellular mechanisms defined, Simon and his team – including Gadi Lalazar, of Rockefeller’s Clinical Scholars Program, and graduate student David Requena – are now working to identify potential targets for drugs to treat the disease.

Among these drug targets is a protein produced from the fused gene that belongs to a family of enzymes called kinases. These enzymes are often mutated in cancers.

The researchers showed that disruption of the fused gene’s kinase activity impaired the formation of tumours in mice – a finding that has strengthened their confidence that agents aimed at targeting this activity or its consequences might be effective against FL-HCC.

The team is also studying the effects of targeting a number of cellular signaling systems that have previously been implicated in other cancers, and that speed tumor growth when they become overactive in FL-HCC patients. And they will be using their new mouse model as a system to test the effectiveness of new therapies prior to initiating clinical trials in patients.